title: Novel targeting of phospho-cMET overcomes drug resistance and induces antitumor activity in multiple myeloma.
abstract: OBJECTIVE
  The aim of the study was to verify the hypothesis that the cMet oncogene is implicated in chemio- and novel drug resistance in multiple myeloma.
  
  
  METHODS
  We have evaluated the expression levels of cMET/phospho-cMET (p-cMET) and the activity of the novel selective p-cMET inhibitor (SU11274) in multiple myeloma cells, either sensitive (RPMI-8226 and MM.1S) or resistant (R5 and MM.1R) to anti-multiple myeloma drugs, in primary plasma cells and in multiple myeloma xenograft models.
  
  
  RESULTS
  We found that resistant R5 and MM.1R cells presented with higher cMET phosphorylation, thus leading to constitutive activation of cMET-dependent signaling pathways. R5 cells exhibited a higher susceptibility to the SU11274 inhibitory effects on viability, proliferation, chemotaxis, adhesion, and to its apoptogenic effects. SU11274 was able to revert drug resistance in R5 cells. R5 but not RPMI-8226 cells displayed cMET-dependent activation of mitogen-activated protein kinase pathway. The cMET and p-cMET expression was higher on plasma cells from patients with multiple myeloma at relapse or on drug resistance than on those from patients at diagnosis, complete/partial remission, or from patients with monoclonal gammopathy of unknown significance. Viability, chemotaxis, adhesion to fibronectin or paired bone marrow stromal cells of plasma cells from relapsed or resistant patients was markedly inhibited by SU11274. Importantly, SU11274 showed higher therapeutic activity in R5- than in RPMI-8226-induced plasmocytomas. In R5 tumors, it caused apoptosis and necrosis and reverted bortezomib resistance.
  
  
  CONCLUSIONS
  Our findings suggest that the cMET pathway is constitutively activated in relapsed and resistant multiple myeloma where it may also be responsible for induction of drug resistance, thus providing the preclinical rationale for targeting cMET in patients with relapsed/refractory multiple myeloma.
authors.affiliation: Internal Medicine Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Moschetta
authors.forename: Antonio
authors.initials: A
authors.lastname: Basile
authors.forename: Arianna
authors.initials: A
authors.lastname: Ferrucci
authors.forename: Maria Antonia
authors.initials: MA
authors.lastname: Frassanito
authors.forename: Luigia
authors.initials: L
authors.lastname: Rao
authors.forename: Roberto
authors.initials: R
authors.lastname: Ria
authors.forename: Antonio Giovanni
authors.initials: AG
authors.lastname: Solimando
authors.forename: Nicola
authors.initials: N
authors.lastname: Giuliani
authors.forename: Angelina
authors.initials: A
authors.lastname: Boccarelli
authors.forename: Fabio
authors.initials: F
authors.lastname: Fumarola
authors.forename: Mauro
authors.initials: M
authors.lastname: Coluccia
authors.forename: Bernardo
authors.initials: B
authors.lastname: Rossini
authors.forename: Simona
authors.initials: S
authors.lastname: Ruggieri
authors.forename: Beatrice
authors.initials: B
authors.lastname: Nico
authors.forename: Eugenio
authors.initials: E
authors.lastname: Maiorano
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.forename: Aldo M
authors.initials: AM
authors.lastname: Roccaro
authors.forename: Angelo
authors.initials: A
authors.lastname: Vacca
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D000970:Antineoplastic Agents; D007211:Indoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D019859:Proto-Oncogene Proteins c-met